A dermatological assessment of pediatric patients with tuberous sclerosis complex (TSC)

Abstract Background Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous syndrome with variable phenotypes. Recent updates of TSC diagnostic criteria reaffirmed the defined genetic diagnostic criterion as the finding of a pathogenic DNA alteration in either TSC1 or TSC2 genes. It also slightly modified definite clinical diagnostic criteria. TSC-associated skin lesions in infancy are important clinical signs to select individuals with possible TSC for a closer clinical follow-up and genetic testing. Objective To raise awareness of the updated TSC diagnosis criteria; to assess the frequency of skin lesions in TSC patients as well as the first dermatological presentation; and to associate the findings with either TSC1 or TSC2 mutations. Methods Observational cross-sectional study. Clinical and genetic data were retrospectively collected from 37 TSC patients from a Brazilian University Hospital. Patients with skin signs were examined and prospectively assessed for 12 months. Results The earliest cutaneous lesions were hypomelanotic macules, which together with angiofibromas were the most frequent dermatological lesions. The total pathogenic DNA alteration ratio between TSC2 and TSC1 genes was 8:1. The frequency of a TSC2 pathogenic variant was 10-fold greater in the presence of ungual fibromas. Study limitations Small sample and a limited number of patients with TSC1 pathogenic variants. Conclusion Clinicians should be knowledgeable about TSC updated diagnostic criteria. Patients need to be followed up by a multidisciplinary team and treated accordingly. Early detection of cutaneous lesions is important for TSC diagnosis. A significant association between TSC2 gene pathogenic alterations and ungual fibromas is described.

A dermatological assessment of pediatric patients with tuberous sclerosis complex (TSC).

BACKGROUND: Tuberous sclerosis complex (TSC) is a multisystem neurocutaneous syndrome with variable phenotypes. Recent updates of TSC diagnostic criteria reaffirmed the defined genetic diagnostic criterion as the finding of a pathogenic DNA alteration in either TSC1 or TSC2 genes. It also slightly modified definite clinical diagnostic criteria. TSC-associated skin lesions in infancy are important clinical signs to select individuals with possible TSC for a closer clinical follow-up and genetic testing. OBJECTIVE: To raise awareness of the updated TSC diagnosis criteria; to assess the frequency of skin lesions in TSC patients as well as the first dermatological presentation; and to associate the findings with either TSC1 or TSC2 mutations. METHODS: Observational cross-sectional study. Clinical and genetic data were retrospectively collected from 37 TSC patients from a Brazilian University Hospital. Patients with skin signs were examined and prospectively assessed for 12 months. RESULTS: The earliest cutaneous lesions were hypomelanotic macules, which together with angiofibromas were the most frequent dermatological lesions. The total pathogenic DNA alteration ratio between TSC2 and TSC1 genes was 8:1. The frequency of a TSC2 pathogenic variant was 10-fold greater in the presence of ungual fibromas. STUDY LIMITATIONS: Small sample and a limited number of patients with TSC1 pathogenic variants. CONCLUSION: Clinicians should be knowledgeable about TSC updated diagnostic criteria. Patients need to be followed up by a multidisciplinary team and treated accordingly. Early detection of cutaneous lesions is important for TSC diagnosis. A significant association between TSC2 gene pathogenic alterations and ungual fibromas is described.

Optical coherence tomography detection of retinal neural loss in patients with tuberous sclerosis.

PURPOSE: Tuberous Sclerosis (TS) is a rare, multisystem genetic disease caused by mutations in the TSC1 and TSC2 genes, leading to abnormalities in cell differentiation and proliferation. This study aimed to evaluate the neural integrity of individuals with TS by using Optical Coherence Tomography (OCT) to examine the peripapillary retinal nerve fiber layer (RNFL) thickness and the macular thickness in patients with TS and to compare with healthy controls. METHODS: Peripapillary and macular OCT scans (Optopol Revo NX SD OCT) were performed on 41 eyes from 22 TS patients, divided into two groups based on the presence of retinal hamartomas, and compared to 20 eyes from a control group. The average peripapillary RNFL thickness was measured for each quadrant. The macular total thickness and ganglion cell layer (GCL) + inner plexiform layer (IPL) thickness were measured based on the Early Treatment Diabetic Retinopathy Study (ETDRS) map. All measurements were then compared between the groups and controls. RESULTS: The TS group showed significantly reduced RNFL thickness and macular thickness when compared to the control group. Specifically, patients with retinal hamartomas exhibited an even more pronounced thinning of both RNFL and macular thickness. CONCLUSIONS: These findings suggest that TS patients undergo significant changes in retinal neurodevelopment and experience axonal loss. This finding may have significant prognostic utility regarding central nervous system degeneration in TS, particularly among patients with retinal hamartomas. OCT may serve as a valuable tool for assessing axonal structural abnormalities in TS patients. TRIAL REGISTRATION NUMBER: Not applicable.

Uncommon Large and Bilateral Fibrous Cephalic Plaques in a Patient with TSC2-Related Tuberous Sclerosis Complex.

Tuberous sclerosis complex (TSC) is a genetic disorder, frequently characterized by early dermatological manifestations. The recognition and adequate description of these dermatological manifestations are of utmost importance for early diagnosis, allowing for the implementation of therapeutic and preventive measures. Fibrous cephalic plaques (FCPs) are considered a major diagnostic criterion for TSC, as FCPs are the most specific skin lesions of TSC. The localization, consistency, color, and size of FCPs vary widely, which can cause diagnostic delay, especially in patients with atypical presentations. The present report describes a female TSC patient with a confirmed heterozygous pathogenic genotype, NG_005895.1 (TSC2_v001): c.2640-1G>T, who presented with uncommon large and bilateral FCPs causing bilateral ptosis and marked with hyperostosis of the diploe that generated an asymmetry of the brain parenchyma. Differential diagnoses considered initially in this patient due to the atypical FCPs are described.

Sporadic lymphangioleiomyomatosis / Linfangioleiomiomatosis esporádica

Abstract Lymphangioleiomyomatosis is a rare multisystemic disease which mainly affects women of reproductive age and is distinguished by diffuse cystic pulmonary involvement. It may present sporadically or in association with tuberous sclerosis complex. Lymphangioleiomyomatosis is also characterized by the presence of extrapulmonary angiomyolipomas, lymphatic tumors, chylothorax and pneumothorax. We present the case of a 39-year-old patient who had had signs and symptoms of pulmonary disease since adolescence, predominantly cough and progressive dyspnea, in addition to fatigue. She had multiple hospitalizations and various diagnoses and treatments without improvement. The clinical history and a high-resolution tomography of the lungs led to a suspicion of the disease, and measurement of vascular endothelial growth factor-D contributed to the diagnosis, with no need for a lung biopsy. (Acta Med Colomb 2022; 48. DOI:https://doi.org/10.36104/amc.2023.2815).

Resumen La linfangioleiomiomatosis es una enfermedad rara multisistémica, que afecta principalmente a mujeres en edad reproductiva y tiene como distintivo un compromiso pulmonar quístico difuso. Se puede presentar de forma esporádica o asociada con el complejo de la esclerosis tuberosa. La linfangioleiomiomatosis se caracteriza además por la presencia de angiomiolipomas extrapulmonares, tumores linfáticos, quilotórax y neumotórax. Se presenta el caso de una paciente de 39 años, que desde su adolescencia viene presentando signos y síntomas de enfermedad pulmonar dados principalmente por tos y disnea progresiva, además de fatiga. Múltiples hospitalizaciones y diversos diagnósticos y tratamientos sin mejoría. Por la historia clínica y la tomografía de alta resolución pulmonar se sospechó la enfermedad, y la determinación del factor de crecimiento endotelial vascular-D contribuyó en el diagnóstico sin nece sidad de biopsia pulmonar. (Acta Med Colomb 2022; 48. DOI:https://doi.org/10.36104/amc.2023.2815).

Tuberous Sclerosis Complex: Prenatal Diagnosis Using Ultrasound and Magnetic Resonance Imaging-A Report of Two Cases.

Tuberous sclerosis complex (TSC) is a multiple system neurocutaneous syndrome with a genetic disorder caused by different mutations in TSC1 or TSC2. Usually, TSC causes tumors in the heart, brain, kidneys, eyes, and lungs. However, tumors can also develop in any other organs. The prenatal diagnosis of TCS is based on the identification of fetal cardiac tumors by ultrasound and brain subependymal nodules, usually identified by fetal magnetic resonance imaging (MRI). We present two case reports of the prenatal diagnosis of TCS using both ultrasound and MRI, which were confirmed by clinical and radiological methods in the postnatal period accordingly.

Clinical, pathological, and molecular correlation of folliculocystic and collagen hamartoma: A new potential diagnostic criterion for tuberous sclerosis complex?

Folliculocystic and collagen hamartoma (FCCH) is a rare entity with only 18 reported cases worldwide. Of them, most are found in patients diagnosed with tuberous sclerosis complex (TSC). FCCH has distinctive histopathologic features, including collagen deposition in the dermis, perifollicular fibrosis, and comedones with keratin-containing cysts lined by infundibular epithelium. We report three patients with a definitive TSC clinical diagnosis in whom clinical, histopathologic, and molecular features were studied to establish if there exists a genotype-phenotype correlation. The molecular results showed different heterozygous pathogenic variants (PV) in TSC2 in each patient: NM_000548.4:c.5024C>T, NG_005895.1:c.1599+1G>T, and NM_000548.4:c.2297_2298dup, to our knowledge; the latter PV has not been reported in public databases. The same PVs were identified as heterozygous in the tumor tissue samples, none of which yielded evidence of a TSC2 second hit. Because all FCCH patients with available molecular diagnosis carry a pathogenic genotype in TSC1 or TSC2, we suggest that FCCH should be considered as a new and uncommon diagnostic manifestation in the TSC consensus international diagnostic criteria. The early recognition of FCCH by clinicians could prompt the identification of new TSC cases. Interestingly, our molecular findings suggest that one of the patients described herein is a probable case of somatic mosaicism.

A novel mutation in the TSC2 gene protects against colorectal cancer in the Mexican population.

INTRODUCTION: Colorectal cancer (CRC) is a complex disease due to the large number of factors that influence its development, including variants in tumor suppressor genes. OBJECTIVE: To estimate allelic and genotypic frequencies of c.3915G>A and c.5371G>A variants of the TSC2 gene in a Mexican population with CRC, as well as to analyze their association with the development of CRC. METHODS: 126 peripheral blood samples from patients diagnosed with sporadic CRC and 134 from healthy individuals, regarded as the control group, were included. Identification of genotypes was carried out using traditional PCR and enzymatic digestion. All individuals signed an informed consent letter. RESULTS: The A allele of the c.3915G>A variant (OR = 0.31, 95% CI = 0.15-0.69, p = 0.004), as well as A/G haplotype of the c.3915G>A and c.5371G>A variants (OR = 0.28, 95% CI = 0.12-0.68, p = 0.005) showed a possible protective effect against sporadic CRC. In silico analysis indicated that both variants generate modifications in the splicing process. CONCLUSION: The presence of TSC2 gene c.3915G>A variant suggests a possible protective effect against sporadic CRC in the Mexican population; however, no association was observed with the c.5371G>A variant.

INTRODUCCIÓN: El cáncer colorrectal (CCR) es una enfermedad compleja debido al gran número de factores que influyen en su desarrollo, incluyendo variantes en genes supresores de tumores. OBJETIVO: Estimar las frecuencias alélicas y genotípicas de las variantes c.3915G>A y c.5371G>A del gen TSC2 en una población mexicana con CCR, así como analizar la asociación con el desarrollo de CCR. MÉTODOS: Se incluyeron 126 muestras de sangre periférica de pacientes con diagnóstico de CCR esporádico y 134 de individuos sanos, considerados como grupo de control. La identificación de los genotipos se llevó a cabo mediante PCR tradicional y digestión enzimática. Todos los individuos firmaron una carta de consentimiento informado. RESULTADOS: El alelo A de la variante c.3915G>A (RM = 0.31, IC 95 % = 0.15-0.69, p = 0.004), así como el haplotipo A/G de las variantes c.3915G>A y c.5371G>A (RM = 0.28, IC 95 % = 0.12-0.68, p = 0.005) mostraron un posible efecto protector contra CCR esporádico. El análisis in silico indicó que ambas variantes generan modificaciones en el proceso de corte y empalme. CONCLUSIÓN: La presencia de la variante c.3915G>A del gen TSC2 sugiere un posible efecto protector contra CCR esporádico en población mexicana; sin embargo, no se observó esta asociación con la variante c.5371G>A.

Use of cannabidiol in the treatment of epilepsy: Lennox-Gastaut syndrome, Dravet syndrome, and tuberous sclerosis complex

SUMMARY OBJECTIVE: The objective of this systematic review with meta-analysis was to evaluate the efficacy, safety, and short- and long-term tolerability of cannabidiol (CBD), as an adjunct treatment, in children and adults with Dravet syndrome (SD), Lennox-Gataut syndrome (LGS), or tuberous sclerosis complex (TSC), with inadequate control of seizures. METHODS: This systematic review was conducted through a search for scientific evidence in the Mediline/PubMed, Central Cochrane, and ClinicalTrials.gov databases until April 2022. Selected randomized clinical trials (RCTs) that presented the outcomes: reduction in the frequency of seizures and total seizures (all types), number of patients with a response greater than or equal to 50%, change in caregiver global impression of change (CGIC) (improvement ≥1 category on the initial scale), adverse events (AEs), and tolerability to treatment. This review followed Preferred Reporting Items for Systematic reviews and Meta-Analyses. RESULTS: Notably, six RCTs were included, with a total of 1,034 patients with SD, LGS, and TSC, of which 3 were open-label extension RCTs. The meta-analysis of the studies showed that the use of CBD as compared with placebo, in patients with convulsive seizures refractory to the use of medications, reduces the frequency of seizures by 33%; increases the number of patients with a reduction ≥50% in the frequency of seizures by 20%; increases the number of patients with absence of seizures by 3%; improves the clinical impression evaluated by the caregiver or patient (S/CGIC) in 21%; increases total AEs by 12%; increases serious AE by 16%; increases the risk of treatment abandonment by 12%; and increases the number of patients with transaminase elevation (≥3 times the referral) by 15%. CONCLUSIONS: This systematic review, with meta-analysis, supports the use of CBD in the treatment of patients with seizures, originated in DS, LGS, and TSC, who are resistant to the common medications, presenting satisfactory benefits in reducing seizures and tolerable toxicity.

Nueva mutación en el gen TSC2 protege contra el cáncer colorrectal en población mexicana / A novel mutation in the TSC2 gene protects against colorectal cancer in the Mexican population

Resumen Introducción: El cáncer colorrectal (CCR) es una enfermedad compleja debido al gran número de factores que influyen en su desarrollo, incluyendo variantes en genes supresores de tumores. Objetivo: Estimar las frecuencias alélicas y genotípicas de las variantes c.3915G>A y c.5371G>A del gen TSC2 en una población mexicana con CCR, así como analizar la asociación con el desarrollo de CCR. Métodos: Se incluyeron 126 muestras de sangre periférica de pacientes con diagnóstico de CCR esporádico y 134 de individuos sanos, considerados como grupo de control. La identificación de los genotipos se llevó a cabo mediante PCR tradicional y digestión enzimática. Todos los individuos firmaron una carta de consentimiento informado. Resultados: El alelo A de la variante c.3915G>A (RM = 0.31, IC 95 % = 0.15-0.69, p = 0.004), así como el haplotipo A/G de las variantes c.3915G>A y c.5371G>A (RM = 0.28, IC 95 % = 0.12-0.68, p = 0.005) mostraron un posible efecto protector contra CCR esporádico. El análisis in silico indicó que ambas variantes generan modificaciones en el proceso de corte y empalme. Conclusión: La presencia de la variante c.3915G>A del gen TSC2 sugiere un posible efecto protector contra CCR esporádico en población mexicana; sin embargo, no se observó esta asociación con la variante c.5371G>A.

Abstract Introduction: Colorectal cancer (CRC) is a complex disease due to the large number of factors that influence its development, including variants in tumor suppressor genes. Objective: To estimate allelic and genotypic frequencies of c.3915G>A and c.5371G>A variants of the TSC2 gene in a Mexican population with CRC, as well as to analyze their association with the development of CRC. Methods: 126 peripheral blood samples from patients diagnosed with sporadic CRC and 134 from healthy individuals, regarded as the control group, were included. Identification of genotypes was carried out using traditional PCR and enzymatic digestion. All individuals signed an informed consent letter. Results: The A allele of the c.3915G>A variant (OR = 0.31, 95% CI = 0.15-0.69, p = 0.004), as well as A/G haplotype of the c.3915G>A and c.5371G>A variants (OR = 0.28, 95% CI = 0.12-0.68, p = 0.005) showed a possible protective effect against sporadic CRC. In silico analysis indicated that both variants generate modifications in the splicing process. Conclusion: The presence of TSC2 gene c.3915G>A variant suggests a possible protective effect against sporadic CRC in the Mexican population; however, no association was observed with the c.5371G>A variant.

COMPLEJO ESCLEROSIS TUBEROSA: a propósito de un caso clínico / TUBEROUS SCLEROSIS COMPLEX: about a clinical case

RESUMEN El Complejo Esclerosis Tuberosa (CET) es un síndrome neurocutáneo multisistémico que pertenece al grupo de las genodermatosis, de transmisión de herencia autosómica dominante con alta penetrancia y muy variable expresividad fenotípica. Es producido por mutaciones en los genes TSC1 y TSC2. Se caracteriza por la triada de epilepsia, retraso madurativo y angiofibromas. El diagnóstico es clínico y consiste en ensamblar los signos clínicos identificados, con los criterios diagnósticos consensuados de criterios principales y secundarios. Presentamos un paciente adulto con antecedentes de retraso madurativo y epilepsia desde la infancia en tratamiento y seguimiento por neurología desde entonces; y antecedentes familiares de síndrome convulsivo en sus hermanos, a quien se le realiza diagnóstico tardío de CET al momento de la consulta, cumpliendo con los criterios para el mismo.

ABSTRACT Tuberous Sclerosis Complex (TSC) is an autosomal dominant multisystem neurocutaneous syndrome with almost complete penetrance but variable expressivity. This genodermatosis occurs upon mutation of TSC1 and TSC2 genes. It is characterized by the classic triad of seizures, mental retardation and cutaneous angiofibromas. The diagnosis of TSC is based by the presence of major and minor criteria. We report the case of an adult male patient with personal history of mental retardation in addition with personal and family history of seizures since childhood.

Everolimus as a possible prenatal treatment of in utero diagnosed subependymal lesions in tuberous sclerosis complex: a case report.

INTRODUCTION: The association between cardiac rhabdomyoma and intraventricular tumors and/or subcortical nodules is characteristic of tuberous sclerosis complex (TSC). Patients with TSC may have refractory seizures, autistic behavior, and cognitive decline. CASE REPORT: The patient received the fetal diagnosis of TSC at the age of 19 weeks of gestations, where presented at prenatal ultrasound cardiac and brain tumors. Fetal MRI showed a lesion in the right and left lateral ventricles near the foramen of Monro associated with subependymal lesions along the entire ependyma of the lateral ventricles and several subcortical tubercles, and the fetal Doppler echocardiogram revealed three cardiac lesions. The fetus underwent intrauterine treatment with everolimus and presented regression and subsequent stabilization of the cardiac and brain lesions; additionally, the patient did not develop seizures or autism and presented good neuropsychomotor development. CONCLUSION: It is the first evidence that mTOR inhibitors may help to prevent neurological complications associated with TSC.

Tuberous Sclerosis Complex with rare associated findings in the gastrointestinal system: a case report and review of the literature.

BACKGROUND: Tuberous Sclerosis Complex (TSC) is a complex and heterogeneous genetic disease that has well-established clinical diagnostic criteria. These criteria do not include gastrointestinal tumors. CASE PRESENTATION: We report a 45-year-old patient with a clinical and molecular diagnosis of TSC and a family history of cancer, presenting two rare associated findings: gastrointestinal polyposis and pancreatic neuroendocrine tumor. This patient was subjected to a genetic test with 80 cancer predisposing genes. The genetic panel revealed the presence of a large pathogenic deletion in the TSC2 gene, covering exons 2 to 16 and including the initiation codon. No changes were identified in the colorectal cancer and colorectal polyposis genes. DISCUSSION AND CONCLUSIONS: We describe a case of TSC that presented tumors of the gastro intestinal tract that are commonly unrelated to the disease. The patient described here emphasizes the importance of considering polyposis of the gastrointestinal tract and low grade neuroendocrine tumor as part of the TSC syndromic phenotype.

Ventricular repolarization abnormalities: the electrocardiographic track of cardiac tumoural involvement in an infant with tuberous sclerosis complex. A case report.

BACKGROUND: Primary cardiac tumours are rare in children. Against this backdrop, Doppler echocardiogram is the main diagnostic procedure, while electrocardiogram (ECG) usually plays a secondary role, by detecting tumoural consequences as cardiac arrhythmias and chambers overload. We describe a case where an electrocardiographic sign was the cornerstone to diagnosis and surveillance of an infant with a cardiac rhabdomyoma. CASE SUMMARY: A female infant was referred for cardiac evaluation to elucidate an electrocardiographic abnormality, detected during investigation of seizures. She had recently been diagnosed with epilepsy and was under three different anticonvulsants for appropriate control. Cardiovascular symptoms were absent. Skin inspection revealed hypochromic macules. Respiratory and cardiovascular examinations were normal, as well as laboratorial tests and chest radiography. Electrocardiogram (ECG) showed dome-shaped ST-segment elevation in V2 and V3. Transthoracic echocardiogram unveiled a single hyper-echogenic node (0.4 cm2) in the interventricular septum. Cardiac chambers had normal size and function and Doppler analysis was also normal. No specific medication was used to treat the tumour. During follow-up, she remained free of cardiac symptoms. Eighteen months after her first visit to the cardiologist, routine clinical assessment, ECG, and transthoracic Doppler echocardiogram normal results stated the spontaneous and complete involution of the tumoural lesion. DISCUSSION: Convex ST-segment elevation, generally related to myocardial injury, is unusual in paediatric patients. Once it occurs in asymptomatic individuals within this age bracket, exclusion of cardiac tumours is mandatory. However, data regarding the accuracy of such electrocardiographic marker in this clinical setting are still to be defined.

Everolimus for cardiac rhabdomyomas in children with tuberous sclerosis. The ORACLE study protocol (everOlimus for caRdiac rhAbdomyomas in tuberous sCLErosis): a randomised, multicentre, placebo-controlled, double-blind phase II trial.

INTRODUCTION: Tuberous sclerosis complex is a rare genetic disorder leading to the growth of hamartomas in multiple organs, including cardiac rhabdomyomas. Children with symptomatic cardiac rhabdomyoma require frequent admissions to intensive care units, have major complications, namely, arrhythmias, cardiac outflow tract obstruction and heart failure, affecting the quality of life and taking on high healthcare cost. Currently, there is no standard pharmacological treatment for this condition, and the management includes a conservative approach and supportive care. Everolimus has shown positive effects on subependymal giant cell astrocytomas, renal angiomyolipoma and refractory seizures associated with tuberous sclerosis complex. However, evidence supporting efficacy in symptomatic cardiac rhabdomyoma is limited to case reports. The ORACLE trial is the first randomised clinical trial assessing the efficacy of everolimus as a specific therapy for symptomatic cardiac rhabdomyoma. METHODS: ORACLE is a phase II, prospective, randomised, placebo-controlled, double-blind, multicentre protocol trial. A total of 40 children with symptomatic cardiac rhabdomyoma secondary to tuberous sclerosis complex will be randomised to receive oral everolimus or placebo for 3 months. The primary outcome is 50% or more reduction in the tumour size related to baseline. As secondary outcomes we include the presence of arrhythmias, pericardial effusion, intracardiac obstruction, adverse events, progression of tumour reduction and effect on heart failure. CONCLUSIONS: ORACLE protocol addresses a relevant unmet need in children with tuberous sclerosis complex and cardiac rhabdomyoma. The results of the trial will potentially support the first evidence-based therapy for this condition.

Complejo de esclerosis tuberosa: perfil neuropsicológico y propuesta de intervención / Tuberous Sclerosis Complex: neuropsychological profile and intervention proposal

El Complejo de Esclerosis Tuberosa (CET) es un trastorno genético de heren-cia autosómica dominante causado por la mutación en uno de los genes TSC1 o TSC2. Los pacientes con una afectación CET grave de tipo neurológica posible-mente presentarán epilepsia, discapacidad intelectual, problemas específicos del aprendizaje y trastornos de la conducta, por lo que la evaluación neuropsicológica en individuos con esta patología cobra un carácter importante al proporcionar información sobre los déficits cognitivos que subyacen en la afectación cerebral, que alteran el funcionamiento intelectual y los aspectos adaptativos. El actual tra-bajo presenta el perfil de una paciente adulta femenina con antecedente de CET, epilepsia y discapacidad intelectual, así como la descripción de una propuesta de intervención neuropsicológica basada en el funcionamiento ejecutivo dorsolateral.

Tuberous Sclerosis Complex (TSC) is an autosomal dominant inherited genetic disorder caused by mutation in one of the TSC1 or TSC2 genes. Patients with severe neurological-type CET involvement may have epilepsy, intellectual disability, specific learning problems, and behavioral disorders. For this reason, the neuropsychological evaluation in individuals with this pathology becomes an important character by providing information on the cognitive deficits that underlie brain involvement that alter intellectual functioning and adaptive aspects. The current work presents the cognitive profile of a female adult patient with a history of TSC, epilepsy and intellectual disability and the description of a proposed neuropsychological intervention based on dorsolateral executive functioning.

Hallazgos clínicos y epidemiológicos en la neurofibromatosis tipo 1 y el complejo esclerosis tuberosa en una serie de pacientes pediátricos / Clinical and epidemiological findings in neurofibromatosis type 1 and tuberous sclerosis complex in a series of pediatric patients

Resumen: Introducción: La neurofibromatosis tipo 1 (NF1) es una entidad genética con una incidencia de 1 entre 2,500 a 3,500 nacimientos. Por su parte, el complejo esclerosis tuberosa (CET) presenta una incidencia de 1 entre 6,000 a 10,000 nacimientos. Ambas entidades neurocutáneas cursan con un patrón de herencia autosómico dominante, expresividad variable y la morbimortalidad se encuentra asociada a complicaciones multisistémicas. El objetivo de este trabajo fue exponer las características clínicas y epidemiológicas de una serie de pacientes pediátricos con diagnóstico de NF1 y CET atendidos en la Unidad de Genética Médica de la Universidad de Los Andes. Métodos: Este trabajo corresponde a una serie de casos de pacientes menores de 16 años atendidos en un período de 11 años, que cumplan con los criterios diagnósticos de NF1 y CET según los consensos para cada entidad. Resultados: Se estudiaron 89 pacientes, 73 con NF1 y 16 con CET. Presentaron dos criterios para NF1, 58 (79.45%) pacientes, y las máculas café con leche fueron las más frecuentes y presentes en todos los casos; 10 pacientes (62.50 %) presentaron dos criterios mayores para el CET, y las máculas hipocrómicas estuvieron igualmente presentes en todos los casos. Conclusiones: Este estudio muestra la forma de presentación clínica de las dos entidades neurocutáneas más frecuentes. Se discuten los criterios diagnósticos con el objeto de identificarlos a edades más tempranas y poder brindar una evaluación médica interdisciplinaria, tratamiento y un oportuno asesoramiento genético familiar.

Abstract: Background: Neurofibromatosis type 1 (NF1) is a genetic entity with an incidence of 1 in 2,500 to 3,500 births. Tuberous sclerosis complex (TSC) has an incidence between 1 in 6,000 to 10,000 births. Both neurocutaneous entities present an autosomal dominant inheritance pattern, variable expressivity and their morbidity and mortality is associated with multisystemic complications. The aim of this study was to present the clinical and epidemiological characteristics of a series of pediatric patients diagnosed with NF1 and TSC, who were treated in the Medical Genetics Unit of the Universidad of Los Andes. Methods: This work corresponds to a series of cases of patients under 16 years of age served in a period of 11 years, who met the diagnostic criteria of NF1 and CET according to the consensus for each entity. Results: We studied 89 patients, 73 with NF1 and 16 with TSC. 58 (79.45%) of the patients presented two criteria for NF1, with café-au-lait macules being the most frequent and present in all cases. 10 (62.50%) of the patients presented two major criteria for TSC; hypochromic macules were equally present in all cases. Conclusions: This study shows the clinical presentation of the two most frequent neurocutaneous entities. Diagnostic criteria are discussed in order to perform them at younger ages and to provide an interdisciplinary medical evaluation, treatment and timely family genetic counseling.

[Hallazgos clínicos y epidemiológicos en la neurofibromatosis tipo 1 y el complejo esclerosis tuberosa en una serie de pacientes pediátricos]. / Clinical and epidemiological findings in neurofibromatosis type 1 and tuberous sclerosis complex in a series of pediatric patients.

Introducción: La neurofibromatosis tipo 1 (NF1) es una entidad genética con una incidencia de 1 entre 2,500 a 3,500 nacimientos. Por su parte, el complejo esclerosis tuberosa (CET) presenta una incidencia de 1 entre 6,000 a 10,000 nacimientos. Ambas entidades neurocutáneas cursan con un patrón de herencia autosómico dominante, expresividad variable y la morbimortalidad se encuentra asociada a complicaciones multisistémicas. El objetivo de este trabajo fue exponer las características clínicas y epidemiológicas de una serie de pacientes pediátricos con diagnóstico de NF1 y CET atendidos en la Unidad de Genética Médica de la Universidad de Los Andes. Métodos: Este trabajo corresponde a una serie de casos de pacientes menores de 16 años atendidos en un período de 11 años, que cumplan con los criterios diagnósticos de NF1 y CET según los consensos para cada entidad. Resultados: Se estudiaron 89 pacientes, 73 con NF1 y 16 con CET. Presentaron dos criterios para NF1, 58 (79.45%) pacientes, y las máculas café con leche fueron las más frecuentes y presentes en todos los casos; 10 pacientes (62.50 %) presentaron dos criterios mayores para el CET, y las máculas hipocrómicas estuvieron igualmente presentes en todos los casos. Conclusiones: Este estudio muestra la forma de presentación clínica de las dos entidades neurocutáneas más frecuentes. Se discuten los criterios diagnósticos con el objeto de identificarlos a edades más tempranas y poder brindar una evaluación médica interdisciplinaria, tratamiento y un oportuno asesoramiento genético familiar. Background: Neurofibromatosis type 1 (NF1) is a genetic entity with an incidence of 1 in 2,500 to 3,500 births. Tuberous sclerosis complex (TSC) has an incidence between 1 in 6,000 to 10,000 births. Both neurocutaneous entities present an autosomal dominant inheritance pattern, variable expressivity and their morbidity and mortality is associated with multisystemic complications. The aim of this study was to present the clinical and epidemiological characteristics of a series of pediatric patients diagnosed with NF1 and TSC, who were treated in the Medical Genetics Unit of the Universidad of Los Andes. Methods: This work corresponds to a series of cases of patients under 16 years of age served in a period of 11 years, who met the diagnostic criteria of NF1 and CET according to the consensus for each entity. Results: We studied 89 patients, 73 with NF1 and 16 with TSC. 58 (79.45%) of the patients presented two criteria for NF1, with café-au-lait macules being the most frequent and present in all cases. 10 (62.50%) of the patients presented two major criteria for TSC; hypochromic macules were equally present in all cases. Conclusions: This study shows the clinical presentation of the two most frequent neurocutaneous entities. Diagnostic criteria are discussed in order to perform them at younger ages and to provide an interdisciplinary medical evaluation, treatment and timely family genetic counseling.

Calcitriol Reverses the Down-Regulation Pattern of Tuberous Sclerosis Complex Genes in an In Vitro Calcification Model.

Tuberous sclerosis complex (TSC) is a neurocutaneous syndrome with autosomal dominant inheritance, and most of the cases are related to loss of function of the TSC1 and TSC2 genes. TSC may occur with a wide range of clinical findings and skin, kidney, brain, and heart are the most commonly affected organs. Brain calcifications in TSC are also described and reported as diffuse and without pattern of symmetry or bilaterality. Recently, a new discovery opened the possibility of using vitamin D (VitD) for treating cerebral calcifications. Calcitriol, the active form of VitD, was able to reduce the calcification in an in vitro model, increasing expression of a gene related to primary familial brain calcification. We show that in the same experimental model, calcitriol was also able to restore and even increase expression of genes related to TSC. This article discusses the use of calcitriol supplementation in patients with TSC, which can be a very interesting strategy due to its low cost and because it is already used in various therapies.